Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women

Am J Hum Genet. 1996 Apr;58(4):803-11.


Late-onset Alzheimer disease (AD) is associated with the apolipoprotein E (APOE)-epsilon4 allele. In late-onset familial AD, women have a significantly higher risk of developing the disease than do men. The aim of this study was to determine whether the gender difference in familial AD is a function of APOE genotype. We studied 58 late-onset familial AD kindreds. Kaplan-Meier survival analysis was used to assess genotype-specific distributions of age at onset. Odds ratios were estimated by logistic regression with adjustment for age and by conditional logistic regression with stratification on families. All methods detected a significant gender difference for the epsilon4 heterozygous genotype. In women, epsilon4 heterozygotes had higher risk than those without epsilon4; there was no significant difference between epsilon4 heterozygotes and epsilon4 homozygotes. In men, epsilon4 heterozygotes had lower risk than epsilon4 homozygotes; there was not significant difference between epsilon4 heterozygotes and those without epsilon4. A direct comparison of epsilon4 heterozygous men and women revealed a significant twofold increased risk in women. We confirmed these results in 15 autopsy-confirmed AD kindreds from the National Cell Repository at Indiana University Alzheimer Disease Center. These observations are consistent with the increased incidence of familial AD in women and may be a critical clue to the role of gender in the pathogenesis of AD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age of Onset
  • Aged
  • Alzheimer Disease / genetics*
  • Apolipoprotein E2
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E / genetics*
  • Family
  • Female
  • Gene Frequency / genetics*
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Odds Ratio
  • Risk Factors
  • Sex Characteristics


  • Apolipoprotein E2
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E